Obesity Induced Adipose Tissue Dysfunction and NAFLD

Obesity is a known risk factor for developing metabolic diseases such as non-alcoholic fatty liver disease (NAFLD)¹. An increasing amount of evidence shows that obesity induced adipose tissue dysfunction and NAFLD development are closely related². Obesity induced changes to adipokine secretion can have detrimental effects on adiponectin and adipose tissue-liver crosstalk, leptin and inflammation, and insulin sensitivity^3,4. Evidence indicates that adipose tissue dysfunction and insulin resistance can impact the regulation of de novo lipogenesis and lead to NAFLD⁵. Since adipokines are essential for adipose tissue-liver crosstalk, the adiponectin to leptin ratio may be a potential biomarker to investigate changes in the adipokines as well as metabolic disturbances caused by obese adipose tissue⁶.

Obesity Induced Changes to Adipokine Secretion

Research demonstrates that obesity has many detrimental effects on adipose tissue (AT), including obesity induced changes to adipokine secretion. Studies illustrate adipose tissue from obese individuals produces an increased amount of proinflammatory adipokines^7,8. Whereas, levels of anti-inflammatory adipokines that promote insulin sensitivity are decreased^7,9. This shift toward proinflammatory adipokines secreted by obese AT promotes a constant state of inflammation^7,9. The excess inflammation can induce more changes to obese AT including:

• Decreased insulin sensitivity^7,10,11
• Increase in lipogenesis^7,10,11
• Macrophage infiltration and proliferation^7,10,11
• Remodeling of the extracellular matrix^7,10,11
• Changes to adipose tissue plasticity^7,10,11

Changes to Adiponectin and Adipose Tissue-Liver Crosstalk

Both the concentration and function of adiponectin are affected by obese adipose tissue. During normal adipose tissue-liver crosstalk, the liver relies on AT to secrete adequate amounts of adiponectin to stimulate β-oxidization and promote insulin sensitivity^3,9. However, studies show that obese individuals have lower levels of adiponectin and, therefore, may only have a limited amount available to perform these duties^3,9. In turn, the body tries to combat the decrease in adiponectin by increasing the amount of insulin secreted by pancreatic β-cells. Over time, the concentration of insulin in circulation increases which can promote the development of insulin resistance².

Changes to Leptin and Inflammation

Leptin concentration and function are also affected by obese adipose tissue. Research indicates that leptin secretion increases with fat mass percentage and obese individuals also have high concentrations of the adipokine^4,12,13. Studies have uncovered that increases in leptin activate the adipokine’s proinflammatory effects on the body⁴. The leptin receptor is expressed by many immune cells such as macrophages and eosinophils⁴. When leptin binds to these immune cells, it promotes the generation of proinflammatory cytokines⁴. The secreted cytokines such as IL-6 and TNF-alpha then promote the secretion of leptin, creating a detrimental inflammation loop⁴. Over time, the combination of inflammation and excessive free fatty acids reduces fatty acid oxidization and promotes insulin resistance⁴.

Obesity Induced Adipose Tissue Dysfunction and NAFLD

Nonalcoholic fatty liver disease is now recognized as a part of metabolic syndrome, and an estimated 20-30% of adults have the disease^14,15. NAFLD is characterized by excessive fat accumulation in the liver not associated with alcohol consumption^14,16. Current research demonstrates that many factors contribute to the development of NAFLD including obesity induced adipose tissue dysfunction¹⁴.

Effects of Obesity Induced Adipose Tissue Dysfunction and Insulin Resistance

Insulin resistance promoted by obesity induced adipose tissue dysfunction is a risk factor for developing NAFLD². Studies reveal that as adipocytes grow larger to accommodate the increased demand for lipid storage, the cytoskeletons of adipocytes can become dysfunctional and impair insulin signaling⁷. As insulin resistance progresses in adipose tissue and throughout the body, pancreatic β-cells increase their secretion to compensate for the elevated need for insulin. The continual high demand for insulin can lead to a decline in β-cell function, health, and mass¹⁷.

Impact of Obesity Induced Adipose Tissue Dysfunction on Liver De Novo Lipogenesis

Research shows that obese adipose tissue and insulin resistance can also negatively impact the regulation of de novo lipogenesis in the liver⁵. Insulin resistance promotes de novo lipogenesis and lipid storage in the liver by:

• Enhancing the expression of lipogenic transcription factors and proteins⁵
• Preventing insulin from inhibiting gluconeogenesis⁵

These occurrences cause an imbalance in both lipid and glucose metabolism. Furthermore, lipid accumulation in the liver driven by insulin resistance can cause inflammation and lead to the development of NAFLD^5,18.

Adiponectin and Leptin as Biomarkers for NAFLD

Both adiponectin and leptin have become key biomarkers in researching metabolic diseases such as NAFLD due to their associations with energy metabolism. Adiponectin and leptin levels have separately been associated with the risk of various metabolic diseases:

• Metabolic syndrome⁸
• Type 2 diabetes¹⁹
• NAFLD progression⁶

The Adiponectin to Leptin Ratio as a Biomarker for NAFLD

Due to variances in the concentrations of adiponectin and leptin, investigations suggest studying the adiponectin to leptin ratio may be better than measuring the adipokines alone. These variances in concentration may be linked to:

• Gender^8,20
• Region^8,20
• Fasting vs postprandial state²⁰

Therefore, the adiponectin to leptin ratio may be beneficial for use in metabolic disease studies investigating fasted vs. fed changes in the adipokine concentrations²⁰. One study shows that the ratio of adipokines is a better noninvasive predictor of NAFLD in obese adolescents than when measured separately²¹. More research is needed, however, to verify that the adiponectin to leptin ratio is a superior biomarker of NAFLD than adiponectin or leptin alone.

Research demonstrates that adipose tissue function can be greatly impacted by obesity. Obesity induced changes to adipokine secretion can interfere with adiponectin and adipose tissue-liver crosstalk^3,9. Additionally, obese adipose tissue can create an imbalance between adiponectin and leptin concentrations, which can lead to a milieu of damaging inflammation and insulin resistance². Adipose tissue dysfunction and insulin resistance can further impair energy balance by promoting de novo lipogenesis in the liver^5,18. Measuring the adiponectin to leptin ratio may be useful in researching obesity induced adipose tissue dysfunction and NAFLD development. However, more research is still needed to understand if the adiponectin to leptin ratio is a better biomarker of NAFLD than measuring each adipokine separately^8,20,21.

References

1. Fabbrini et al. (2010). Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic and clinical Implications. Hepatology. 2010 Feb;51(2):679–689. PMCID: PMC357509.
2. Combs & Marliss. (2014). Adiponectin signaling in the liver. Rev Endocr Metab Disord. 2014 Jun;15(2):137-47. doi: 10.1007/s11154-013-9280-6. PMID: 24297186.
3. Rui. (2014). Energy metabolism in the liver. Compr Physiol. 2014 Jan;4(1):177-97. PMID: 24692138.
4. Paz-Filho et al. (2012). Leptin: Molecular mechanisms, systemic pro-inflammatory effects, and clinical implications. Arquivos Brasileiros de Endocrinologia & Metabologia. 56(9):597-607. org/10.1590/S0004-27302012000900001.
5. Sanders & Griffin. (2016). De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol Rev Camb Philos Soc. 2016 May;91(2):452–468. doi: 1111/brv.12178. PMCID: PMC4832395.
6. Polyzos et al. (2010). The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab. 2010 May;12(5):365-83. PMID: 20415685.
7. Choe et al. (2016). Adipose tissue remodeling: Its role in energy metabolism and metabolic disorders. Metabolism and Metabolic Disorders. Front. Endocrinol. 7:30. PMCID: PMC4829583.
8. Lopez-Jaramillo et al. (2014). The role of leptin/adiponectin ratio in metabolic syndrome and diabetes. Horm Mol Biol Clin Investig. 2014 Apr;18(1):37-45. PMID: 25389999.
9. Stern et al. (2016). Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab. 2016 May 10;23(5):770-84. PMID: 27166942.
10. Pellerginelli et al. (2016). Adipose tissue plasticity: How fat depots respond differently to pathophysiology. Diabetologia 2016 Jun;59(6):1075-88. PMID: 27039901.
11. Badimon & Cubedo. (2017). Adipose tissue depots and inflammation: Effects on plasticity and resident mesenchymal stem cell function. Cardiovasc Res. 2017 Jul 1;113(9):1064-1073. PMID: 28498891.
12. Maffei et al. (1995). Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Medicine. 1995;1:1155–1161. PMID: 7584987.
13. Allison & Myers. (2014). 20 Years of leptin – Connecting leptin signaling to biological function. J Endocrinol. 2014 Oct;223(1):T25-35. PMID: 25232147.
14. Buzzetti et al. (2016). The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016 Aug;65(8):1038-48. PMID: 26823198.
15. Kitade et al. (2017). Nonalcoholic fatty liver disease and insulin resistance: New insights and potential new treatments. Nutrients. 2017 Apr;9(4):387. PMCID: PMC5409726.
16. Axley et al. (2017). Non-alcoholic fatty liver disease. Gastroenterology and Endoscopy News. October 2017;15:95-120.
17. Prentki & Nolan. (2006). Islet β cell failure in type 2 diabetes. J Clin Invest. 2006 Jul 3;116(7):1802–1812. PMCID: PMC1483155.
18. Nguyen et al. (2008). Liver lipid metabolism. J Anim Physiol Anim Nutr (Berl). 2008 Jun;92(3):272-83. PMID: 18477307.
19. Polyzos et al. (2016). Circulating leptin in non-alcoholic fatty liver disease: A systemic review and meta-analysis. Diabetologia. 2016 Jan;59(1):30-43. PMID: 26407715.
20. Srikanthan et al. (2016). Systematic review of metabolic syndrome biomarkers: A panel for early detection, management, and risk stratification in the West Virginian population. Int J Med Sci. 2016;13(1):25–38. PMCID: PMC4716817.
21. Angin et al. (2014). Leptin-to-adiponectin ratio in obese adolescents with nonalcoholic fatty liver disease. Turk J Pediatr. 2014 May-Jun;56(3):259-66. PMID: 25341597.